(a) Field of Invention
The invention relates to the use of transdermal delivery devices for controlled administration through the skin of benzothiazepine calcium antagonists to maintain a sustained systemic therapeutic amount of the drug for an extended period of time in a patient. More particularly, the invention relates to transdermal administration of (+)(2S,3S)-3-acetoxy-8-chloro-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-me thoxyphenyl) -1,5-benzothiazepin-4-(5H)-one for treatment of diseases such as hypertension, angina and convulsions.
(b) State of the Art
Pharmaceutically active drugs are commonly administered to patients in need of treatment in periodic doses given orally or by injection to maintain adequate systemic therapeutic levels of the drug. For a variety of reasons, it is often advantageous to administer certain drugs, e.g. drugs which act on the cardiovascular system, in a single daily oral or injected sustained release dose. However, many drugs are not efficiently administered in such a single daily dosage regimen, because of incomplete absorption from the gastrointestinal tract and/or so-called first-pass metabolism by the liver.
As a result of these problems, techniques for administering drugs by absorption through the skin to afford sustained systemic levels in a patient have been developed. In accordance with these techniques, transdermal delivery devices have been developed which administer a wide variety of drugs, including hormones, antibiotics, vasoactive drugs and others. Transdermal devices for administering nitroglycerine and scopolamine are commercially available at present.
In a transdermal device, the drug is commonly incorporated into a polymeric reservoir material, such as a silicone elastomer or acrylic polymer matrix, for controllable release of the drug through the skin. See, e.g., U.S. Pat. Nos. 3,996,934 and 4,460,371 which teach such devices. The device also has means by which it may be affixed to the skin of the patient for delivery of the drug. Experimentation to determine which delivery system is best for a particular drug is often required, however, because it is well known that a particular transdermal delivery system which is useful with one drug, may not be useful with others.
Moreover, as disclosed in U.S. Pat. No. 4,615,699, incorporation of permeation enhancers into the transdermal delivery system is often required to potentiate or enhance permeation of the drug through the skin to obtain effective serum levels. For example, U.S. Pat. No. 4,645,502 teaches a transdermal delivery device for efficient delivery of highly ionized fat insoluble drugs, including the ionized forms (i.e., salts) of various drugs. The invention is premised on the observation that unionized forms of most drugs are more permeable through skin than their ionized forms, i.e., generally the salt of a particular drug cannot be delivered through the skin, absent some way of enhancing permeation. The '502 patent provides such a transdermal delivery device which incorporates a permeation enhancer element to achieve efficient permeation of ionized drugs through the skin.
Transdermal delivery of vasodilator drugs, primarily nitroglycerine, and other cardiovascular drugs such as beta receptor antagonists (e.g., propranolol) and cardiac glycosides (e.g., digoxin) is particularly attractive as a means of maintaining sustained levels of such drugs in a patient. A variety of devices for delivering such drugs has been developed. See e.g., U.S. Pat. Nos. 4,460,562, 4,573,996 and 4,668,232 and published European Application No. 0159168.
Calcium antagonists are an important group of vasodilators which have found wide clinical use in the treatment of cardiovascular problems, such as angina and hypertension. Chemically, calcium antagonists form a diverse group of organic compounds, all of which inhibit the flux of calcium ions through calcium channels in cell membranes. Four chemical classes of calcium antagonists are generally recognized: (1) the dihydropyridines, exemplified by nifedipine and nimodipine; (2) the phenylalkylamines, such as verapamil; (3) the diphenylalkylamines, such as flunarizine and (4) the benzothiazepines, such as diltiazem. Generally, such drugs are orally administered to a patient, often in several doses per day to maintain adequate therapeutic levels. A once a day sustained release dosage, if feasible, would be preferable for these drugs, however.
Various devices which can provide transdermal delivery of calcium antagonists have been developed. For example, U.S. Pat. No. 4,637,930 discloses transdermal delivery of nicardipine hydrochloride, which has both cerebral and coronary vasodilating properties. Because of the drug's poor permeability through skin, however, the '930 patent teaches that permeability enhancers, including propylene glycol, 2-4 carbon monohydric alcohols, thioglycol, 6-12 carbon mono- and di-fatty acid esters of glycerol, 6-12 carbon mono- and di-fatty acid esters of sorbitol and urea, must be included in the transdermal delivery system to promote or potentiate permeation of the drug through the skin in order to achieve adequate serum levels for therapy.
Likewise, U.S. Pat. No. 4,668,232 provides an improved transdermal delivery system where drugs, including vasodilators, are present in a rubber and adhesive reservoir together with a water-swellable polymer to enhance permeation of the incorporated drug. The device can be used to administer calcium antagonists, with verapamil being exemplified.
U.S Pat. No. 4,690,683 specifically teaches a transdermal delivery device for administration of verapamil at a high rate of delivery. Verapamil, as a free base, is dispersed in an electroneutral lipophilic polymer matrix, e.g., a silicone elastomer. According to this patent, the verapamil should exist essentially in its electrically neutral non-ionic form (i.e., verapamil base) in order for the drug to be efficiently released from the polymer matrix (col. 4, lines 5-20). Enhancing agents, such as a saturated aliphatic alcohol, may be included in the delivery system to enhance permeation of the drug.
Nifedipine and other dihydropyridine calcium antagonists which have been incorporated into transdermal delivery systems are disclosed in Japanese applications, Derwent Nos. 61129140 and 58038213. These references also teach various enhancing agents to potentiate drug permeation.
Several references have disclosed transdermal devices for delivery of diltiazem. For example, European Patent Application No. 0159168 discloses a "soft patch" device comprising a drug, a water soluble protein having an absorption promoting effect (i.e., a permeation enhancer), a polyhydric alcohol, a tackifier and an oleaginous substance. Numerous drugs, including diltiazem and other calcium antagonists, either in a non-ionized form or as an ionized acid or base addition salt form, can be used in the delivery system.
Transdermal delivery of diltiazem hydrochloride is also the subject of Japanese unexamined Patent Disclosure No. 132828-1987. The reference acknowledges the poor percutaneous absorption of diltiazem hydrochloride which is due to its hydrophilic nature and teaches that absorption of the drug may be enhanced by the inclusion of non-ionic water soluble macromolecules in the delivery system.
Recently, several new 8-chloro-1,5-benzothiazapine derivatives with calcium channel blocking activity have been described. A particularly promising drug with potent vasodilating activity for treatment of hypertension and angina is (+)(2S,3S)-3-acetoxy-8-chloro-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-me thoxyphenyl)-1,5-benzothiazepin-4-(5H)-one ("TA-3090"), exemplified in U.S. Pat. No. 4,567,175. However, a once-a-day oral dose of TA-3090 to achieve a sustained systemic therapeutic level does not appear to be feasible because of incomplete oral absorption and/or first pass metabolism of the drug by the liver.